Yuejun Liu

Association of Adipose Tissue and Liver Fibrosis With Tissue Stiffness in Morbid Obesity: Links With Diabetes and BMI Loss After Gastric Bypass

CONTEXT Liver and white adipose tissue (WAT) develop inflammation and fibrosis. OBJECTIVE The aim of the study was to evaluate the bioclinical relevance of WAT fibrosis in morbid obesity and diabetes and the relationships with tissue stiffness measured using a novel device. DESIGN AND SETTING Observational and longitudinal studies were conducted in a hospital nutrition department. PATIENTS Biopsies of liver and subcutaneous WAT (scWAT) and omental adipose tissue were collected from 404 obese bariatric surgery candidates, of whom 243 were clinically characterized before surgery and 3, 6, and 12 months after surgery. In 123 subjects, liver and scWAT stiffness was assessed noninvasively using vibration-controlled transient elastography (VCTE). INTERVENTIONS Bariatric surgery was performed for some patients. MAIN OUTCOME MEASURE Adipose tissue fibrosis and stiffness and their link to obesity phenotypes were measured. RESULTS scWAT fibrosis was positively associated with liver fibrosis (fibrosis score ≥2) (ϱ= 0.14; P = .01). VCTE-evaluated liver and scWAT stiffness was positively correlated with immunohistochemistry-determined liver (ϱ= 0.46; P = .0009) and scWAT fibrosis (ϱ= 0.48; P = .0001). VCTE-evaluated scWAT stiffness measures negatively associated with dual-energy x-ray absorptiometry-evaluated body fat mass (R = -0.25; P = .009) and were correlated with metabolic variables. Diabetic subjects showed increased scWAT stiffness. Participants less responsive to gastric bypass were older and more frequently diabetic, and they had increased body mass index, serum IL-6, and scWAT and liver fibrosis. Subjects with no diabetes and normal liver had higher fat mass and lower tissue fibrosis and stiffness. CONCLUSION scWAT stiffness was associated with tissue fibrosis, obesity, and diabetes-related traits. Noninvasive evaluation of scWAT stiffness might be useful in clinical practice.

Accumulation and Changes in Composition of Collagens in Subcutaneous Adipose Tissue After Bariatric Surgery.

CONTEXT Extracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored. OBJECTIVE The objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS. MAIN OUTCOME MEASURES scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls. RESULTS Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163(+) cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase [LOX], LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation. CONCLUSIONS After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss.

A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα+) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα+ cells with high CD9 expression (CD9high) originates pro-fibrotic cells whereas their CD9low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα+ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

Relevance of omental pericellular adipose tissue collagen in the pathophysiology of human abdominal obesity and related cardiometabolic risk

Background:Adipose tissue fibrosis is a relatively new notion and its relationship with visceral obesity and cardiometabolic alterations remains unclear, particularly in moderate obesity.Objective:Our objective was to examine if total and pericellular collagen accumulation are relevant for the pathophysiology of visceral obesity and related cardiometabolic risk.Subjects and methods:Surgical omental (OM) and subcutaneous (SC) fat samples were obtained in 56 women (age: 47.2±5.8 years; body mass index (BMI): 27.1±4.4 kg/m2). Body composition and fat distribution were measured by dual-energy X-ray absorptiometry and computed tomography, respectively. Total and pericellular collagen were measured using picrosirius red staining. CD68+ cells (total macrophages) and CD163+ cells (M2-macrophages) were identified using immunohistochemistry.Results:We found that only pericellular collagen percentage, especially in OM fat, was associated with higher BMI, body fat mass and adipose tissue areas as well as lower radiologic attenuation of visceral adipose tissue and altered cardiometabolic risk variables. Strong correlations between peri-adipocyte collagen percentage and total or M2-macrophage percentages were observed in both depots. Total collagen percentage in either compartment was not related to adiposity, fat distribution or cardiometabolic risk.Conclusions:As opposed to whole tissue-based assessments of adipose tissue fibrosis, collagen deposition around the adipocyte, especially in the OM fat compartment is related to total and regional adiposity as well as altered cardiometabolic risk profile.

The FAT Score, a Fibrosis Score of Adipose Tissue: Predicting Weight-Loss Outcome After Gastric Bypass

Context Bariatric surgery (BS) induces major and sustainable weight loss in many patients. Factors predicting poor weight-loss response (PR) need to be identified to improve patient care. Quantification of subcutaneous adipose tissue (scAT) fibrosis is negatively associated with post-BS weight loss, but whether it could constitute a predictor applicable in clinical routine remains to be demonstrated. Objective To create a semiquantitative score evaluating scAT fibrosis and test its predictive value on weight-loss response after Roux-en-Y gastric bypass (RYGB). Methods We created a fibrosis score of adipose tissue (FAT score) integrating perilobular and pericellular fibrosis. Using this score, we characterized 183 perioperative scAT biopsy specimens from severely obese patients who underwent RYGB (n = 85 from a training cohort; n = 98 from a confirmation cohort). PR to RYGB was defined as <28% of total weight loss at 1 year (lowest tertile). The link between FAT score and PR was tested in univariate and multivariate models. Results FAT score was directly associated with increasing scAT fibrosis measured by a standard quantification method (P for trend <0.001). FAT score interobserver agreement was good (κ = 0.76). FAT score ≥2 was significantly associated with PR. The association remained significant after adjustment for age, diabetes status, hypertension, percent fat mass, and interleukin-6 level (adjusted odds ratio, 3.6; 95% confidence interval, 1.8 to 7.2; P = 0.003). Conclusion The FAT score is a new, simple, semiquantitative evaluation of human scAT fibrosis that may help identify patients with a potential limited weight-loss response to RYGB.

AdipoScan™ - A novel transient elastography based tool to assess subcutaneous adipose tissue shear wave speed in morbidly obese patients

Subcutaneous white adipose tissue (scWAT) in human obesity undergoes severe alterations such as fibrosis accumulation. Fibrosis in scWAT is related to metabolic alterations and to less efficiency in losing weight after bariatric surgery. There is currently no non-invasive tool to assess subcutaneous white adipose tissue (scWAT) characteristics. A novel device named AdipoScan™ based on vibration controlled transient elastography (VCTE™) was developed by Echosens so as to assess scWAT shear wave speed (SWS). In the present study, the prototype and how it has been adapted to scWAT SWS evaluation was first described. Repeatability was then assessed in terms of coefficient of variation (CV) with and without repositioning on tissue mimicking phantoms (~1% and 0%, respectively) and in vivo on 41 volunteers (14% and 7%, respectively). Then, scWAT SWS was measured in vivo on 73 morbidly obese patients candidate to bariatric surgery. scWAT SWS is significantly associated with tissue fibrosis, gender, body fat mass assessed by DXA, hypertension status, and biological parameters such as glycemia, lipid profile, hepatic parameters and adiponectin. Results suggest that scWAT evaluation before surgery can be useful in clinical practice to help phenotype obese patients and the stage of adipose tissue alterations.